Impurity
Profiling
Impurities in pharmaceuticals are unwanted chemicals
that remain with the Active
Pharmaceutical Ingredients (APIs) or develop during formulation or develop
upon ageing of both APIs and formulated APIs to medicines. In the pharmaceutical
world, an impurity is considered as any other inorganic or organic material, or
residual solvents other than the drug substances, or ingredients, arise out of
synthesis or unwanted chemicals that remains with APIs. Impurity profiling includes identification, structure elucidation
and quantitative determination of impurities and degradation products in bulk
drug materials and pharmaceutical formulations. Impurity profiling has gained
importance in modern pharmaceutical analysis due to the fact that unidentified,
potentially toxic impurities are hazardous to health and in order to increase
the safety of drug therapy, impurities should be identified and determined by
selective methods.
Organic impurities are often free radicals from by-products, intermediates, or degradation products. Inorganic impurities include transition metals, reagents, and ligands.
The presence of these unwanted chemicals even
in small amounts may influence the efficacy and safety of the pharmaceutical
products. Different pharmacopoeias such as British pharmacopoeia (BP) and the
United States pharmacopoeia (USP) are slowly incorporating limits to allowable
levels of impurities present in the APIs or formulations.
The control of impurities in Formulated
products and Active Pharmaceutical ingredient’s were regulated by various
regulatory authorities like ICH, USFDA, Canadian Drug and Health Agency are
emphasizing on the purity requirements and the identification of impurities in Active Pharmaceutical
Ingredient’s (API’s).
Terms used by various regulatory
bodies and ICH to describe the impurities as follows;
1. Intermediate
2.
Penultimate intermediate
3.
By-products
4.
Transformation products
5.
Interaction products
6.
Related products
7.
Degradation products
Methods to Identify the Impurities:
1. Reference standard method
Reference standards serve as the basis of
evaluation of both process and product performance and are the benchmarks for
assessment of drug safety. This method is not only for
the active ingredients in dosage forms but also for impurities, degradation products, starting materials, process
intermediates, and excipients.
2. Spectroscopic method
Spectroscopy methods are UV, IR, MS, NMR and
Raman spectroscopy.
3. Separation method
The Capillary electrophoresis (CE), Chiral
Separations, Gas Chromatography (GC), Supercritical Fluid Chromatography (SFC),
TLC, HPTLC, HPLC are used for separation of impurities and degradation
products.
4. Isolation method
Solid-phase extraction methods ; Liquid-liquid
extraction methods ; Accelerated solvent extraction methods ; Supercritical
fluid extraction ; Column chromatography ; Flash chromatography ;TLC ;GC ;HPLC
; HPTLC ;Capillary electrophoresis (CE) ;Supercritical fluid chromatography
(SFC) .
5. Characterization method
Characterization methods highly associated sophisticated
instrumentation, such as MS attached to a GC or HPLC, are inevitable tools in
the identification of minor components (drugs, impurities, degradation
products, metabolites) in various matrices. For characterization of impurities,
different techniques are used; which are as follows;
NMR-Nuclear Magnetic Resonance
Spectroscopy
The ability of NMR to provide information
regarding the specific bonding structure and stereochemistry of molecules of
pharmaceutical interest has made it a powerful analytical instrument for
structural elucidation
MS-Mass Spectroscopy
It has an increasingly significant impact on
the pharmaceutical development process over the past several decades. Advances
in the design and efficiency of the interfaces, that directly connect
separation techniques with Mass Spectrometers have afforded new opportunities
for monitoring, characterizing, and quantification of drugrelated substances in
active pharmaceutical ingredients and pharmaceutical formulations.